The cardiovascular effects of acetylcholine include alterations in automaticity, conduction, coronary blood flow and contractility. Although marked differences are apparent with respect to these actions, little consensus regarding mechanism has been reached. The present investigation is directed toward an analysis of differences between muscarinic effects on cardiac automaticity and conduction. Recent evidence suggests that potential inhomogeneities in muscarinic receptor behavior might underlie some of these differences. Moreover, we have found that cholinergic efficacy at the sinus node is profoundly modulated by the perfusion characteristics of acetylcholine delivered through the sinus node artery. Whether this factor contributes to differences in cholinergic responsiveness is, however, unknown. Thus, experiments are planned which will analyze potential interrelationships between pharmacological and mechanical effects of acetylcholine on the sinus and AV nodes. Agonist and/or antagonist drugs will be administered via the sinus and AV node arteries under rigidly controlled perfusion conditions. The differences between muscarinic responses to vagal stimulation and exogenous agonist administration will be explored. Additional experiments will ascertain whether differences in complex autonomic interactions (ie: accentuated antagonism) are responsible for differences in cholinergic efficacy at the sinus and AV nodes. The information derived from these studies will be of importance in delineating more clearly the complex effects of parasympathetic activation on the heart. Further understanding of parasympathetic mechanisms involved in normal cardiac function (automaticity and conduction) is essential for a complete understanding of the alterations in neural control evident in pathophysiological states. The possibility for the existence of inhomogeneities in muscarinic receptor subtypes within the heart may provide the impetus for the development of new pharmacologic agents which could selectively influence cholinergic function in the heart.